Mixing and delivering system

ABSTRACT

An apparatus for separately storing a first component, such as a drug and for mixing this first component with a second component, such as a sterilized diluent, to form a beneficial agent which can be delivered to a patient from the container containing the second component. The device includes novel means for interconnecting a container, such as a glass vial containing a first component, such as a drug, with a second container such as a flexible bag containing the second component such as a parenteral liquid, and then for mixing the components under sterile conditions.

BACKGROUND OF THE INVENTION

This is a continuation in part application of co-pending applicationSer. No. 07/903,651, filed Jun. 24, 1992.

FIELD OF THE INVENTION

The present invention relates generally to component mixing. Moreparticularly, the invention concerns an apparatus for separately storinga first component, such as a drug and for mixing this first componentwith a second component, such as a sterilized diluent, to form abeneficial agent which can be delivered to a patient from the containercontaining the second component. The device includes novel means forinterconnecting a container, such as a glass vial containing the firstcomponent, with a flexible bag containing the second component and thenfor mixing the components under sterile conditions.

DISCUSSION OF THE INVENTION

In the past, pharmaceuticals have been provided by drug manufacturers insterilized vials, typically of glass construction. When thepharmaceuticals are in powder form, they are generally administered tothe patient within a carrier liquid by standard intravenous procedures.Such carrier liquids include saline solution, dextrose solution andsterilized water.

Mixing of the powdered pharmaceuticals with the carrier liquid has beenaccomplished in several ways many of them being quite crude. Forexample, a common practice is to inject a quantity of the liquid carrierinto the vial to dissolve the powdered component. Then using a cannulaand syringe, the solution thus formed is injected into a largercontainer such as a flexbag containing the liquid carrier. This methodis quite tedious and provides substantial opportunities forcontamination and error.

In those instances where the pharmaceutical must be diluted beforedelivery to a patient, as is the case with powered pharmaceuticals, thepharmaceutical can also be injected directly into a container of diluentand the container then interconnected with a suitable administration setfor intravenous delivery of the solution to a patient. As a generalrule, the diluent is packaged in glass bottles, or flexible plasticcontainers such as those sold under the names MINI-BAG™ and VIAFLEX® byTravenol Laboratories, Inc. of Deerfield, Ill. These containers areconveniently provided with administration ports for connection to theadministration set which delivers the container contents from thecontainer to the patient. The pharmaceutical is typically added to thecontainer through some type of an inlet port or vial receptacle providedon the container.

Because infusion of medicaments is most often accomplished in a hospitalenvironment, it is the nurse, doctor or medical technician who mixes thedrug and diluent usually at one time shortly before administration ofthe drug to the patient. This mixing step can be time consuming andhazardous, as for example, when toxic drugs are involved. Further, sincemany of the prior art mixing devices are crude and imprecise, accurate,sterile and thorough mixing of the drug and the diluent is mostdifficult and time consuming. Accordingly, such devices are not wellsuited for use in the home environment.

Several types of closed drug delivery systems which are somewhat moresophisticated have recently been made available. These systems typicallycomprise a flexible container such as a plastic bag to which a glassdrug vial can be easily coupled. The flexible container usually containsa liquid diluent and often includes a frangible member that allows fluidpassage only when broken. As a general rule, when the drug vial iscoupled with the flexible container, the stopper of the drug vial ispierced and the frangible member ruptured so as to allow sterilecommunication between the drug vial and the liquid diluent contents ofthe flexible container. Mixing of the drug with the diluent isaccomplished by manipulation of the flexible container. Exemplary ofprior art systems of this character are those disclosed in U.S. Pat. No.4,583,971 issued to Bocquet, et al. and in U.S. Pat. No. 4,606,734issued to Lyons. The Lyons apparatus includes a compressible chamberwith a liquid component therein, the compressible chamber including gastrapping and reservoir compartments in open communication. The gastrapping compartment can be connected to a container such as a drug vialhaving a mixing component therein. After a pathway between the vial andthe gas trapping compartment is opened, mixing is accomplished throughmanipulation of the compressible chamber.

Another very successful prior art, dual container system is described inU.S. Pat. Nos. 4,614,267 issued to Larkin and 4,614,515 issued to Trippand Larkin. In this system, a flexible diluent container includes atubular port which provides means for securing thereto a stopperedmedicament vial as well as a stopper removal means. The stopper removalmeans includes an engagement element, or extractor, which is attached toa removable cover and seals the inner end of the port. In use, as thevial is advanced into the tubular port, the vial stopper moves intoengagement with the extractor which grips the stopper enabling it to bepulled from the vial as the cover is pulled from the port. Once thestopper has been removed from the vial, the powered contents of thevial, such as a lyophilized drug, can be dumped into the diluent in thebag and mixed therewith through manipulation of the bag.

Still another type of component mixing device is disclosed in U.S. Pat.No. 4,467,588 issued to Carveth. The Carveth device includes two sealedchambers having a frangible sterilized connection therebetween. Onechamber carries the liquid component and the other carries a sealed vialcontaining the second component. The frangible connection provides asterile pathway for intermixing the components.

The apparatus of the present invention offers numerous advantages overthe prior art devices by providing a closed system for separatelystoring and selectively intermixing a wide variety of different types ofmedicaments and other beneficial agents with a diluent or otherparenteral fluid under completely sterile conditions. The beneficialagents, such as drugs and biologically active materials are typicallyimmobilized on a suitable substrate which is preferably stored within aglass vial until shortly before the time that the beneficial agent is tobe administered to the patient. The vial along with the substrate can bequickly and easily interconnected with a sterile chamber which isdisposed in fluid communication with the diluent chamber of a flexiblebag so that the substrate can be presented to the diluent in a manner topermit separation and release of the beneficial agent and its thoroughmixing with the diluent.

SUMMARY OF THE INVENTION

The preferred form of the apparatus of the present invention forintermixing first and second components includes a flexible containerhaving a fluid reservoir for containing a liquid component, such as adiluent. In fluid communication with the reservoir is a sterile mixingchamber into which the assembly containing the first component, such asa beneficial agent, can be introduced. The assembly carrying thebeneficial agent includes a support structure to which the beneficialagent is removably affixed and a housing, such as a glass vial, whichserves to contain the support structure within a sealed, sterileenvironment. Upon mating the assembly with the flexible container, thesubstrate carrying the beneficial agent is automatically moved into aposition within the mixing chamber so that the substrate is directlyexposed to the fluid reservoir that contains the diluent. Uponappropriate manipulation of the flexible container, the diluent willflow through and about the substrate in a manner such that thebeneficial agent, removably carried thereby, is separated from thesubstrate and thoroughly intermixed with the diluent to form thesolution to be delivered to the patient via an administration set thatis connected to the flexible container.

It is an object of the present invention to provide an apparatus of thecharacter described in the preceding paragraph which provides theopportunity to add to a diluent or other parenteral fluid containedwithin a flexible solution container (flexbag), selected elements,chemical compounds and biologically active materials, including drugs,medicaments, biological agents, and other therapeutic agents(additives). This addition is accomplished by removably affixing theselected additives to various forms of support structures which can beplaced within a mixing chamber disposed proximate the liquid reservoirof the flexbag and in the path of the fluid forced from the fluidreservoir when the flexbag is manipulated. In this way, the diluentwithin the flexbag can expeditiously be rendered therapeutically activeupon hydration of the additive carried by the substrate which isdisposed within the mixing chamber.

Another object of the invention is to provide an apparatus of thecharacter described in which the adding means, including the substratewhich carries the first component, or additive, is maintained within acompletely sterile environment, such as a sealed or stoppered glassvial, until immediately prior to the controlled mixing of the first andsecond components.

Another object of the invention is to provide an apparatus of the classdescribed in which a wide variety of selected additives can be removablyaffixed to the substrate that is introduced into the mixing chamber ofthe flexbag assembly for controlled intermixing with the liquidcontained within the fluid reservoir of the flexbag assembly.

Another object of the invention is to provide a device of theaforementioned type in which toxic or other hazardous compounds,including those with short therapeutic lives can be separately andsafely stored until immediately prior to their use following beingintermixed with the liquid compound contained with the separate flexiblebag container.

Another object of the invention is to provide a device of the characterdescribed in the preceding paragraph in which toxic or other hazardouscompounds which are to be intermixed with the liquid component can beseparately and safely handled during the manufacture of the substrateportion of the device and in which the substrate carrying the hazardousmaterials can, following manufacture, be safely stored within a sealedglass vial until time of use.

Another object of the invention is to provide a device of the classdescribed in which the additive or beneficial agent components, such asa drug, can be uniformly deposited or otherwise removably affixed to theadditive support in a manner to maximize immediate and substantiallycomplete separation of the additive and complete intermixing thereofwith the liquid component.

Still another object of the invention is the provide a device of thecharacter described in the preceding paragraphs which is easy to use, ishighly reliable, and is inexpensive to produce in quantity so that thedevice can be disposed of after use.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a generally perspective exploded view of one form of themixing and delivery system of the present invention.

FIG. 2 is an enlarged cross-sectional view of the container such as aclosed and stoppered glass vial which contains one of the components tobe mixed.

FIG. 3 is a cross-sectional view similar to FIG. 2, but showing thecontainer containing the second component after the protective coverwhich seals the container has been removed.

FIG. 4 is an end view of the container shown in FIG. 3.

FIG. 5 is an end view of the transport disc of the apparatus which iscarried within the inlet of the container, such as a flexible bag, whichcontains the first component to be mixed.

FIG. 6 is a cross-section view taken along lines 6--6 of FIG. 5.

FIG. 7 is a fragmentary generally perspective view illustrating themanner in which the container containing the first component isinterconnected with the transport disc of the second container.

FIG. 8 is a cross-sectional view of the upper mixing chamber of thecontainer, such as a flexible bag, that contains the first componentshowing the transport disc in an initial position within the inlet ofthe mixing chamber.

FIG. 9 is a cross-section view taken along lines 9--9 of FIG. 8.

FIG. 10 is a cross-sectional view illustrating the initial mating of thecontainer containing the first component with the transport disc of thecontainer containing the second component.

FIG. 11 is a fragmentary view similar to FIG. 10 but illustrating themovement of the components of the container containing the firstcomponent as the container is mated with the container containing thesecond component.

FIG. 12 is a cross-sectional view of an alternate form of the container,such as a glass vial, which contains the first component to be mixed.

FIG. 13 is a cross-sectional view similar to FIG. 12 but showing theappearance of the container after the sealing cap has been removed.

FIG. 14 is a fragmentary, cross-sectional view of an alternate form ofthe second container of the apparatus, such as a flexible bag,illustrating the construction of the mixing chamber which, in thisinstance, is generally vertically oriented rather than horizontallyoriented as was the case with the first embodiment of the invention.

FIG. 15 is a fragmentary cross-sectional view illustrating the mating ofthe container containing the first component with the containercontaining the second component.

FIG. 16 is an exploded generally perspective view of the alternate formof the container which contains the first component illustrating themanner in which the container containing the second component isinterconnected.

FIG. 17 is a generally perspective view of various configurations ofsupports adapted to removably carry the first component.

FIG. 18 is a cross-sectional view of still another form of thecontainer, such as a glass vial, which contains the first component tobe mixed.

FIG. 19 is a cross-sectional view similar to FIG. 18 but showing theappearance of the container after the sealing cap has been removed.

FIG. 20 is a fragmentary, cross-sectional view of still another form ofthe second container of the apparatus, such as a flexible bag,illustrating the construction of the mixing chamber.

FIG. 21 is a fragmentary cross-sectional view illustrating the mating ofthe container containing the first component with the containercontaining the second component.

FIG. 22 is a cross-sectional view of yet another form of the container,such as a glass vial, which contains the first component to be mixed.

FIG. 23 is a fragmentary, cross-sectional view of yet another form ofthe second container of the apparatus, such as a flexible bag,illustrating the construction of the mixing chamber which, in thisinstance, comprises a bellows-like structure.

FIG. 24 is a fragmentary cross-sectional view showing the firstcontainer or glass vial assembly initially mated with the secondcontainer and with the bellows-like structure compressed.

FIG. 25 is a view similar to FIG. 24 but showing the bellows-likestructure expanded to permit intermixing of the first and secondcomponents.

FIG. 26 is a generally perspective, exploded view of another form of themixing and delivery system of the present invention.

FIG. 27 is an enlarged fragmentary, cross-sectional view of the lowerportion of the flex bag shown in FIG. 26.

FIG. 28 is a fragmentary, cross-sectional view of the upper portion ofthe container shown in FIG. 26 which contains the first component to beintermixed with the second component contained within the flex bag.

FIG. 29 is a cross-sectional view taken along lines 29--29 of FIG. 30.

FIG. 30 is a fragmentary view partly in section illustrating the mannerin which the container containing the first component is interconnectedwith the second container containing the second component.

FIG. 31 is a fragmentary, cross-sectional view of the spike port whichcomprises a part of the container containing the first component.

FIG. 32 is a generally perspective view of the various additionalsubstrate constructions of the invention.

FIGS. 33, 34, 35, and 36 are general diagrammatic views illustratingvarious means for affinity attachment of ligands, protein molecules andenzymes to the substrates.

DESCRIPTION OF THE INVENTION

In the paragraphs which follow, wherein the apparatus of the inventionwill be discussed, the following terms will have the following meanings:

Element--any of the fundamental substances that consist of atoms of onlyone kind and that singly or in combination constitute all matter.

Additive--the element, compound, substance, agent, biologically activematerial, or other material which is to be added to the fluid containedin the reservoir of the device of the invention.

Parenteral Fluid--any solution which may be delivered to a patient otherthan by way of the intestines, including water, saline solutions,alkalizing solutions, dextrose solutions, acidifying solutions,electrolyte solutions, reagents, solvents and like aqueous solutions.

Beneficial Agents--any drug, medicament, pharmaceutical, medicalpolymer, enzyme, element, chemical compound or other material useful inthe diagnosis, cure, mitigation, treatment or prevention of disease andfor the maintenance of the good health of the patient.

Biologically Active Material--a substance which is biochemically,immunochemically, physiologically, or pharmaceutically active orreactive. Biologically active material includes at least one or more ofthe following: biochemical compounds (such as amino acids,carbohydrates, lipids, nucleic acids, proteins, and other biochemicalsand substances which may complex or interact with biochemicalcompounds), such biochemical compounds biologically functioning asantibodies, antigenic substances, enzymes, co-factors, inhibitors,lectins, hormones, hormone producing cells, receptors, coagulationfactors, anti-fungal agents, growth enhancers, histones, peptides,vitamins, drug, cell surface markers and toxins, among others known tothose skilled in the art. Of the group of biologically active materialsdescribed, proteins are of utmost current interest because of the largemolecule genetically engineered biopharmaceuticals as those species tobe immobilized on the additive carriers hereinafter to be described. Adiscussion of the use of biomosic polymers as carriers for biologicallyactive materials is set forth in European Patent Application 0,430,517A2.

Adding Means--an additive and any means for presenting the additive tothe fluid flowing through the fluid passageways of the fluid deliverydevice of the invention in a manner such that all or any part of theadditive will be added to the fluid. The adding means comprises theadditive and the additive presentation means which may take the form ofa functional support, or carrier, an anchorage, a deposition site orelement holder, with or without some type of intermediate matrix.

Additive Presentation Means--any means such as a functional support orsubstrate for presenting the additive to the fluid flowing through thedevice. The functional substrate can comprise a polymer, copolymer, andinter-polymer, a ceramic, a crystal sponge, a carbon based matrix, acelullosic, glass, plastic biomosaic polymers, azlactone-functionalpolymer beads, adduct beads, carboxylate-functional polymer beads, gums,gels, filaments and like carriers.

The adding means of the invention can take several different forms suchas those illustrated in FIG. 17. However, in its preferred form, theadding means comprises a cylindrically shaped, microporous, polymericfunctional support structure 12 (FIG. 2) to which various additives,including beneficial agents such as drugs, biologically activematerials, and various chemical elements and compounds can be releasablyconnected. Structure 12 can include porous channels that extendcompletely through the substructure forming micropores on the surface ofthe polymers and throughout the substrate structure. These additives arecarried by the structure in a manner such that, as the liquid containedwithin the second container, which may comprise a diluent, a reagent orother aqueous solvent, flows around, about and through the supportassembly, in the manner presently to be described, the additives will bepresented to the liquid, separated from the support assembly andefficiently added and intermixed with the liquid.

The additives themselves can also take various physical forms includingliquid, solid, granular, powder, particle, microparticles, gel, waxhydrocolloid carriers, such a gum film, tablet, crystalline, emulsions,microcrystalline, microcapsules, microspherical, spray dried compoundsand lypohilized compounds and saturants. The additives can be removablyconnected to, immobilized on, impregnated within or supported by supportmeans in a number of ways. The additives can be chemically ormechanically attached, affixed, or bound directly or indirectly throughcooperation with an intermediate matrix. They can be captured, affixed,linked, or cross-linked, anchored to the surfaces of the support, orsurface active agent, or they can be absorbed, reaction catalyzed,electrostatically encapsulated, attached by chemical modification in tothe carrier surface, polymerized on or through the carrier, localized,entrapped, deposited suspended or occluded within voids, cells, tubulesand interstices formed in the support. One important method forremovably affixing the additive to the functional support means includestreating the functional support means with a compound having reactivefunctional groups such as azlactone functional compounds with their highbinding capacity. In certain applications, the biologically activematerial can be bound at the surfaces of biomosaic polymers in themanner described in EPO Patent No. 0 430 517 A2. Similarly, graftcopolymers can be used in the manner described in U.S. Pat. No.5,013,795 issued to Coleman, et al. In this way complexing agents,catalysts and biological materials such as enzymes or other proteins aswell as biomacromolecules can be attached to the carrier.

Similarly, the additives can be immediately separated from thefunctional support and added to or intermixed with the liquid flowingthrough the device by one or more of various mechanisms, includingchemical reaction, dissolution, debinding, delinking bioseparation,diffusion, washing, disintegration, erosion, disassociation, desorbsion,solubilization, leeching, enzymatic cleavage, biological reaction,osmosis, separated from ring opening materials and like separationmeans.

Referring now to the drawings and particularly to FIGS. 1 and 2, oneform of the apparatus of the invention for controllably intermixing thefirst component with the second liquid component comprises a container14 having a fluid reservoir portion 16 for containing the secondcomponent and a mixing chamber 18 within which the first and secondcomponents can be intermixed. Reservoir portion 16 is formed by sealablyinterconnected flexible walls 16a and mixing chamber 18 is formed byrigid walls 19 (FIGS. 8 and 9). As best seen in FIG. 9, chamber 18 is influid communication with the upper end of reservoir portion 16.Container 14 further includes top, bottom and side edges 14a, 14b, and14c with mixing chamber 18 being disposed proximate top edge 14a andextending generally parallel to top and bottom edges 14a and 14b.

The apparatus also comprises adding means, as earlier defined herein,for presenting the first component to the second component forintermixing the two components. In the embodiment of the invention shownin FIGS. 1 and 2, the adding means comprises the previously identifiedsupport 12 upon which the first component is removably affixed. Theadding means also includes a container assembly 20 for containingsupport 12 and connector means for connecting the container assembly 20to the mixing chamber so that support 12 can be exposed to fluidintroduced into the mixing chamber upon manipulation of the flexiblecontainer 14. Container 14 is preferably constructed of flexible plasticsheets which are interconnected along their edges in a manner well knownin the art to form the fluid reservoir. The mixing chamber preferablycomprises a tubular shaped plastic structure which is sealablyencapsulated within the container body in a manner well known to thoseskilled in the art.

As best seen in FIG. 2, container assembly 20 comprises a glass vial 22which is surrounded by a protective covering 24, such as a thin plastic.Protective covering 24 is fabricated in two parts and includes a bodyportion 24a which encapsulates the non-threaded body portion 22a of theglass vial and a removable cover portion 24b which initially sealablyencapsulates the threaded, open end 22b of the glass vial.Circumscribing cover 24 is a label 26. Provided on covering 24intermediate its ends are a plurality of circumferentially spacedlocking teeth 27, the purpose of which will presently be described.

As illustrated in FIG. 1, protective cover 24b comprises a tear-off typeportion which can be removed from the glass vial assembly by pulling ona tear tab 24c. Similarly, the opening, or inlet port, of the mixingchamber portion of the flexible container 14 is initially sealed by asterile tear-off cap 28. These types of tear off caps are of a characterwell known in the art.

Referring to FIGS. 3 and 4 it can be seen that after tear-off cover 24bis removed from the vial assembly, external threads 30, which areprovided on glass vial 22, are exposed. Similarly, the forward most, oroutboard extremity 12a of support assembly 12 is exposed. Turning toFIG. 7 it can be seen that outboard end 12a of support 12 is uniquelyconfigured to include perpendicularly disposed, diametrically-extendingridges 32 and 34. Provided proximate the crossing point of ridges 32 and34 is an umbrella-like locking protuberance 36 which is adapted tointerlock within a cavity 37 provided in a transport disc 38. Transportdisc 38 is initially positioned within the inlet port 40 of mixingchamber 18 and functions to seal the mixing chamber to atmospherefollowing removal of the tear cap 28 (see also FIG. 8). Disc 38 is alsoprovided with a pair of perpendicularly extending grooves 41 which areadapted to closely receive ridges 32 and 34 when the support isconnected to the disc.

Turning now particularly to FIG. 8, wall 19 of mixing chamber 8 isprovided with two sets of internal threads identified by the numerals 42and 44 respectively which are of substantially different pitch withthreads 44 having a considerably greater pitch than threads 42. Threads42 are adapted to mate with external threads 30 provided on vial 22 toenable interconnection of the container assembly 20 with the flexiblebag 14. On the other hand, transport disc 38 is adapted to mate withcoarse threads 44. For this purpose, circumferentially spaced roundedprotuberances are provided on disc 38a (FIGS. 5 and 7), whichprotuberances are closely receivable within threads 44. In this regardit is to be noted that disc 38 is initially positioned within threads 44at a location proximate the inlet port 40 of the mixing chamber. Aspreviously mentioned, with this construction, the inlet port remainssealed to atmosphere when cover 28 is removed, thereby preventing theinterior of chamber 18 from becoming contaminated prior to the containerassembly being connected to the flex bag in a manner next to bedescribed.

In using the apparatus of the present invention, tear cap 24b is firstremoved from the vial assembly 20 by griping tear strip 24c (FIG. 1) andpulling outwardly. With cap 24b removed, the container assembly has theappearance shown in FIG. 3. Next, the flex bag port cover or cap 28 isremoved from the inlet port of the flexible bag assembly 14 so as toexpose the mouth of the port in the manner illustrated in FIG. 1. Asindicated in FIG. 9, disc 38, which is preferably assembled with theflex bag subassembly at the time of its manufacture, rests within theoutboard end of threads 44 and functions to sealably close inlet port 40to atmosphere. Transport disc 38 comprises a portion of the transportmeans of the present embodiment of the invention and, in a mannerpresently to be described, functions to advance support 12 inwardly ofthe mixing chamber upon rotation of vial 22 relative to the connectorport or inlet port 40 of the flex bag 14.

Turning now to FIG. 10, mating of the container assembly 20 with theflex bag assembly 14 is accomplished by inserting the outboard, orthreaded end of the glass vial 22 into port 40 in the manner shown inFIG. 10. Upon insertion of the container assembly 20 into the connectorport, threads 30 will mate with threads 42 and simultaneously theforward end 12a of support 12 will move into engagement with transportdisc 38. As the forward end 12a of the support 12 moves into mixingchamber 18, ridges 32 and 34 will be received within grooves 41 andprotuberance 36, which is provided on the support 12, will be lockablyreceived within aperture 37 provided on disc 38. Umbrella-shapedprotuberance 36 will be securely interlocked within aperture 37 of disc38, which aperture is configured in the manner best seen in FIG. 6 tolockably engage protuberance 36 so that the resiliently deformableflange portion 36a of the protuberance will prevent withdrawal ofsupport 12 from the transport disc.

With the container assembly 20 in the position shown in FIG. 10,rotation of the assembly will cause the component parts of the assemblyto move inwardly into the mixing chamber in the manner shown in FIG. 11.More particularly, threads 30 which are provided on the glass vial willadvance within internal threads 42 provided proximate the inlet port orconnector port of flex bag assembly 14. At the same time ridges 32 and34, which have been received with channels 41 of the transport disc,will impart rotation to disc 38. Because threads 44 are much more coarsethan threads 42, rotation of the container assembly 20 will cause disc38 and support 12, which is interconnected therewith by protuberance 36,to advance rapidly within chamber 18 from the first position shown inFIG. 10 to the second position shown in FIG. 11. As support 12 advances,it will move telescopically outwardly of the internal chamber 22a ofglass vial 22, with the resiliently deformable, piston-like end portion12c sliding along the internal wall of chamber 22a. At the point atwhich support 12 reaches the second position shown in FIG. 11, lockingprotuberances 27 provided on container assembly 20 will interlock withgrooves 49 provided within inlet port 40 (FIG. 1) thereby locking thecontainer assembly to the flex bag.

It should be noted that transport disc 38 is also provided with anumbrella-like protuberance 50 which is lockably receivable within acorresponding configured aperture 52 provided in end wall 19a of mixingchamber 18. Once again, protuberance 50 and its receptacle or aperture52 are so configured that upon movement from the first position shown inFIG. 10 to the second position shown in FIG. 11, support 12 will besecurely locked in place within the mixing chamber in the manner bestseen in FIG. 11. In this position the open end of vial 22 sealablyengages an internal shoulder 18a provided on the mixing chamber.

With support 12 securely locked and fluid-tight sealed into positionwithin mixing chamber 18, and with container assembly 20 lockablyconnected and fluid-tight sealed to inlet port 40 of the flex bag,manual manipulation of the flexible film portion of side walls 16a ofthe reservoir portion 16 of the flexible bag will cause the fluid withinthe reservoir, such as a diluent or other parenteral fluid, to flow intomixing chamber 18 and rapidly move around, about and through substrate12 in a manner to expeditiously and completely remove the additive fromthe substrate and thoroughly intermix it with the liquid component.

After the first and second components have been substantially mixed andthe combined solution thus formed has returned to reservoir 16, thesolution can be withdrawn from the flex bag through an appropriateadministration set (not shown) that has been interconnected with outletport 55 (FIG. 1).

Referring now to FIGS. 12 through 16 and particularly to FIG. 16,another form of the apparatus of the invention for controllablyintermixing the first component and the second liquid component is thereshown. This embodiment is similar to the previously discussed embodimentand comprises a flexible container 60 having a fluid reservoir portion62 with flexible side walls 62a for containing the second component.Container 60 also has a mixing chamber 64 formed by rigid walls 66. Asbefore, chamber 64 is in fluid communication with reservoir portion 62via open side portions 64a. In this later form of the invention, it isto be observed that the mixing chamber extends generally perpendicularto, rather than parallel with, top and bottom edges 60a and 60b. Savefor this fact this second embodiment of the invention is of basicallythe same construction and operates in essentially the same way as theembodiment of the invention shown in FIGS. 1 through 12. Accordinglylike numbers are used in FIGS. 12 through 16 to identify likecomponents.

As best seen in FIG. 12, the container assembly 68 of this embodiment ofthe invention comprises a glass vial 70 which carries within itsinternal chamber a support 72. Vial 70 is surrounded by a plasticovercover sheath 74 which includes a body portion 74a which encapsulatesthe non-threaded body portion 70a of the glass vial and a portion 74bwhich sealably encapsulates the threaded, open end 70b of the glassvial. Circumscribing the intermediate portion of covering 74 is a collarhaving circumferentially spaced locking teeth 77 of the characterpreviously described and as shown in FIG. 1 for locking the containerassembly to the flexible bag. Overcover 74 is constructed in two matingparts which are appropriately bonded together.

Overcover 74b comprises a tear-off type cover end portion which, asbefore, can be removed from the glass vial assembly by pulling on a teartab 74c (FIG. 16). Similarly, the opening, or inlet port, of the mixingchamber portion of the flexible container is initially sealed by asterile tear-off cap 60c of the same type illustrated in FIG. 1 and of acharacter well known in the art.

Referring to FIG. 13 it can be seen that after tear-off cover portion74b is removed from the vial assembly, external threads 80 which areprovided on glass vial 70, are exposed. Similarly, the downwardlyextending, or outboard extremity 72a of support 72 is exposed. Theoutboard end 72a of support 72 is configured in the same manner as end12b of support 12 and interlocks within a cavity 37 provided intransport disc 38 which is carried within the inlet port of mixingchamber 64.

Mixing chamber 64 is also provided with two sets of internal threadswhich cooperate with threads 80 and with disc 38 in the same manner aspreviously described in connection with the earlier embodiment.

In using the apparatus of this second form of the intention, tear cap74b is first removed from the vial assembly and the flex bag port coveror cap is removed from the inlet port 81 of the flexible bag assembly 68so as to expose the vertically extending mouth of the port in the mannerillustrated in FIG. 14. As indicated in FIG. 14, disc 38, rests withinthe outboard end of threads 44 and functions to sealably close inletport 81 to atmosphere. As before, disc 38 functions to advance support72 inwardly of the mixing chamber upon rotation of vial 70 relative tothe connector port or inlet port 81 of the flex bag.

Turning to FIGS. 14 and 15, mating of the container assembly 68 with theflex bag assembly is accomplished as before by inserting the outboard,or threaded end of the glass vial 70 into port 81. Upon insertion of thecontainer assembly into the connector port, threads 80 will mate withthe first internal threads 83 and the forward end of support 72 willmove into locking engagement with transport disc 38. As the forward endof the support moves into the mixing chamber, protuberance 85 which isprovided on the support 72, will be lockably received within aperture 37provided in disc 38. Rotation of the container assembly will cause thecomponent parts of the assembly to move downwardly into the mixingchamber in the manner shown in FIG. 15. More particularly, threads 80which are provided on the glass vial will advance within internalthreads 83 provided proximate the inlet port or connector port of flexbag assembly. At the same time ridges 32 and 34, which have beenreceived with channels 41 of the transport disc, will impart rotation todisc 38 with the resiliently deformable, piston-like end portion of thesupport sliding along the internal wall of chamber 22a. At the same timethat support 12 reaches the second position shown in FIG. 11, lockingprotuberances 76 provided on container assembly 68 will interlock withgrooves 79 provided within inlet port 81. Continued rotation of thecontainer assembly 68 will cause disc 38 and support 72, which isinterconnected therewith by protuberance 36 to advance rapidly withinchamber 64 from a first position to a second position shown in FIG. 15.As support 72 advances into the mixing chamber, it will movetelescopically outwardly of the internal chamber of the glass vial.

once again, since transport disc 38 is provided with a generallyumbrella-shaped protuberance 50 which is lockably receivable within anaperture 87 provided in end wall 64b of the mixing chamber, movementfrom the first starting position to the second position shown in FIG.15, will result in support 72 being securely locked in place within themixing chamber in the manner best seen in FIG. 15.

With support 72 securely locked into position within mixing chamber andwith container assembly 68 lockably connected to inlet port 81 of theflex bag, manual manipulation of the side walls of the reservoir portionof the flexible bag will cause the fluid within the reservoir, such as adiluent or other parenteral fluid, to flow into mixing chamber 64 andrapidly move around, about and through support 72 in a manner toexpeditiously release and substantially remove the additive from thesupport and thoroughly intermix it with the liquid.

After the first and second components have been mixed and the solutionthus formed has returned to reservoir 62, the solution can be withdrawnfrom the flex bag through an appropriate administration set (not shown)that has been interconnected with outlet port 90 (FIG. 16).

Turning to FIGS. 18 through 21 still another form of the apparatus ofthe invention for controllably intermixing the first component with thesecond liquid component is there shown. This embodiment is similar tothe previously discussed embodiment and like numbers are used toidentify like components. This latest embodiment also comprises aflexible container 60 having a fluid reservoir portion 62 for containingthe second component (FIGS. 20 and 21). Container 60 also has an openingor inlet port 91 provided at the top of the bag and extending generallyperpendicular to the top edge thereof. Inlet port 91 is sealed by atearaway closure 91a which is readily removable as before. Port 91 is influid communication with reservoir portion 62 and, in a manner presentlyto be described, the container assembly of this later form of theinvention is movable directly into the reservoir for component mixing.

As best seen in FIG. 18, the container assembly 92 of this embodiment ofthe invention comprises a glass vial 94 which carries within itsinternal chamber a functional support assembly 96. Vial 94 is surroundedby a two part protective covering 98 which includes a body portion 98awhich encapsulates the non-threaded body portion 94a of the glass vialand a cover 98b which sealably encapsulates the threaded, open end 94bof the glass vial. Circumscribing cover 98 is a medicament primary label99. As before, covering 98 includes an enlarged diameter portion havingteeth 100 which irreversibly engage an annular female spline 101.

Protective cover 98b comprises a tear-off type cover which, as before,can be removed from the glass vial assembly by pulling on a tear tab. Inthis latter form of the invention, the opening, or inlet port, of themixing chamber portion of the flexible container is initially sealed bya frangible membrane 102 of the type illustrated in FIG. 20.

Referring to FIG. 19 it can be seen that after tear-off cover 98b isremoved from the vial assembly, external threads 104 which are providedon glass vial 94, are exposed. Similarly, the downwardly extending, oroutboard extremity 96a of support assembly 96 is exposed. The outboardend 96a of support 96 is here provided in the form of an elastomersstopper like member 106 which is sealably received within the open endof glass vial 94 in the manner shown in FIG. 19. Member 106 includes asupport means here shown as an outwardly extending column 106aterminating in an annular retention collar 106b. The end 106c of stopper106 comprises a generally conically shaped portion having a membranepiercing point 108a. As best seen in FIG. 19, the body of the stopper isprovided with a thread 108.

The inlet port assembly of this form of the invention is provided withtwo sets of internal threads which cooperate with threads 104 and withthread 108 in a manner presently to be described. More particularly, asbest seen in FIG. 20, the inlet port includes a neck-like portion havingthreads 111 which cooperate with threads 104 of the glass vial. The necklike portion also includes a sleeve-like member 114 having a neckportion with a coarse thread 113 and a body portion having matingthreads 113a. Threads 113 and 113a cooperate with thread 108 of stopper106.

In using the apparatus of this second form of the invention, the tearcap is first removed from the vial assembly and the flex bag port coveror cap 91a is removed from the inlet port 91 of the flexible bagassembly 60 so as to expose the vertically extending mouth of the port.As indicated in FIG. 20, membrane 102 is positioned within the outboardend of the inlet port and, until ruptured, functions to sealably closethe port to atmosphere.

Turning particularly to FIGS. 20 and 21, mating of the containerassembly 92 with the flex bag assembly is accomplished as before byinserting the outboard, or threaded end of the glass vial 98 into port91. Upon insertion of the container assembly into the connector port,threads 104 will mate and seal with first internal thread 111 providedin the inlet port assembly and thread 108 will mate with thread 113provided in the neck portion of sleeve 114. As the forward end of thestopper 106 moves into the mixing chamber, point 108a will rupturefrangible membrane 102 and continued rotation of the container assemblywill cause the component parts of the assembly to move downwardly intoreservoir 62 in the manner shown in FIG. 21. More particularly, threads104 which are provided on the glass vial will advance within internalthreads 111 provided proximate the inlet port or connector port of flexbag assembly. At the same time, thread 108 will mate with threads 113and 113a causing support structure 96 and stopper 106 to move out of theopen end of the glass vial and travel rapidly downwardly into reservoir62. As the support structure assembly advances into the mixing chamber,support 96 will move telescopically outwardly of the internal chamber ofthe glass vial and stopper 106 will pierce frangible membrane 102.Continued rotation of the glass vial assembly 98 will cause downwardextension of the support assembly until teeth 100 engage spline 101 andstopper 106 engages stop 115 which is located at the inboard terminus ofsleeve 114.

With support 96 depending into reservoir 62 in the manner shown in FIG.21, manual manipulation of the side walls of the reservoir portion ofthe flexible bag will cause the fluid within the reservoir, such as adiluent or other parenteral fluid, to flow around, about and throughfunctional support 96 in a manner to expeditiously separate releaseremove the additive from the support and thoroughly intermix it with theliquid.

After the first and second components have been mixed and the solutionthus formed can be withdrawn from the flex bag through an appropriateadministration set (not shown).

Turning to FIGS. 22 through 25 still another form of the apparatus ofthe invention for controllably intermixing the first component with thesecond liquid component is there shown. This embodiment comprises acontainer 120 having a fluid reservoir portion 121 for containing thesecond component (FIG. 23). Container 120 is provided with a uniquelyconfigured, outwardly extending mixing chamber 122, formed by abellows-like, collapsible wall 124 (see FIGS. 23 and 25) which dependsfrom an upper, connector collar 125. The lower end of wall 124terminates in a cylindrically-shaped collar 123 which is connected tothe upper end of the flex bag. Chamber 122 is in fluid communicationwith the reservoir portion of the container via fluid passageways 126provided in a transverse wall 127 which extends across collar 128. Onceagain, as indicated in FIG. 23, the mixing chamber extends generallyperpendicular to, rather than parallel with, top and bottom edges of thecontainer 120.

As best seen in FIG. 22, the container assembly 130 of this embodimentof the invention comprises a glass vial 132 which carries within itsinternal chamber a support assembly 134. Vial 132 is surrounded by aprotective covering 136 which includes a body portion 136a whichencapsulates the closed end portion 132a of the glass vial and a cover136b which sealably encapsulates the open end 132b of the glass vial.Circumscribing cover 74 a medicament primary label 139. Cover 136includes an enlarged diameter portion 138 having locking teeth 139, thepurpose of which will presently be described. Protective cover 136bcomprises a tear-off type cover which, as before, can be readily removedfrom the glass vial assembly.

Fluid passageways 126 which are provided in transverse wall 127 areinitially sealed by a disc shaped elastomeric or plastic member 142 ofthe configuration shown in FIG. 23. Member 142 had a centralprotuberance 142a which is frictionally received within an aperture 143provided in wall section 12. In a manner presently to be described,fluid passageways 126 can be opened for fluid flow by pushing downwardlyon protuberance 142a of disc 142 with sufficient force to free it fromaperture 143 and to cause it to separate from wall section 127 in themanner illustrated in FIG. 24.

Referring particularly to FIG. 24 it can be seen that after the tear-offcover is removed from the vial assembly, a depending column 146 isexposed. Column 146 is an extension of a central column 146a which formsa central core of cylindrically shaped functional support assembly 134.Provided at the lower extremity of column 146 is a disc engaging means147 which is adapted to engage protuberance 142a of the sealing disc.Also provided proximate the lower end of the column is a locking means,shown here as a generally umbrella-shaped segment 148, which is lockablyreceived within a cavity 149 provided in wall section 127.

In using the apparatus of this latest form of the invention, tear cap136b is first removed from the vial assembly and the flex bag port coveror cap 150 (FIG. 23) is removed from the inlet connector collar 125 ofthe flexible container so as to expose the vertically extending mouth ofthe mixing chamber. As indicated in FIG. 23, sealing disc 142 isinitially connected to wall 127 and functions to sealably closepassageways 126 until the container assembly 130 can be mated with theflex bag assembly.

Turning to FIG. 24, mating of the container assembly 130 with the flexbag assembly is accomplished by inserting the outboard, or threaded endof the container assembly into connector port 125. Upon insertion of thecontainer assembly into the connector port, external threads 160provided on the glass vial will mate with internal threads 162 formed inconnector collar 125 so that rotation of the vial will threadablyinterconnect the vial with the connector collar. As the containerassembly is threadably received into and sealed with the connector port,column 146 will enter the bellows 124 and its lower extremity willengage protuberance 143 of disc 142. A downward force exerted on thecontainer assembly will cause the bellows to collapse from the firstposition shown in FIG. 23 to the second position shown in FIG. 24. Asthe bellows-like wall is compressed column 146 will move downwardlyforcing disc 142 to separate from wall 127 thereby opening fluidpassageways 126. As the disc is separated, umbrella-like segment 148 ofcolumn 146 will enter into locking engagement with the appropriatelyshaped locking cavity 149 formed in wall 127 thereby interlockingtogether support assembly 132 and wall 127.

With the container assembly threadably secured within the mouth of theflexible container, relaxation of the downward pressure being exerted onthe container assembly will cause bellows 124 to return to the expandedposition shown in FIG. 25. As the bellows expands, support 134 willsimultaneously move telescopically outwardly of vial 132 and into opencommunication with the interior of mixing chamber 122. Upon inversion ofthe flexible container to insure contact with the reservoir contents,the bellows expansion will cause the fluid within the reservoir, such asa diluent or other parenteral fluid, to flow rapidly into mixing chamber122 via passageways 126 and to rapidly move around, about and throughfunctional support means 134. As the fluid moves around and through thesupport, additive will be expeditiously separated, released andsubstantially removed from the support and thoroughly intermixed withthe liquid in reservoir 121.

After the first and second components have been mixed and the solutionthus formed has returned to the reservoir of the flex bag, the solutioncan be withdrawn therefrom through an appropriate administration set(not shown).

Various forms of adding means and additive assemblies of the characterillustrated in FIG. 17 can be used with each of the previously describedembodiments. For example, the assemblies can comprise a porous substratewith interconnecting voids that include porous channels in itssubstructure which can extend completely throughout the substructurelayer forming micro- and macro-pores on the surface and in thesubstructure. The substrate can comprise a crystal sponge 172 over whichvarious outer coatings, 172b of one or more additives are bonded.Particularly useful in the form of the invention shown in FIG. 16 whenthe bottom wall of the mixing chamber is open, is a solid tubular membersuch as member 174 which has an internal, axially extending fluidpassageway 174a, the inner wall of which, along with the outer wall ofthe tubular member, is lined with a separation coating or surface activeagent or intermediate matrix affixing the additives such as medicaments,drugs and other beneficial agents can be used.

Still another form of additive assembly is of the character identifiedin FIG. 17 by the numeral 176. This assembly comprises a cylindricalmember made up of a multiplicity of fused together microspheres 176a,each of which is coated with a surface active agent separation coatingupon which is deposited and chemically anchored a biologically activematerial or other beneficial agent.

The additive assembly 178 of FIG. 17 comprises a cylindrically shapedstructure made up of a plurality of interconnected bundles 178a theexposed surfaces of which carry the selected additive which has beenremovably interconnected thereto as a coating, vapor deposition or otherchemical attachment.

Still another additive assembly 180 comprises a cylindrically shapedporous structure which is provided with pores 180a of varying sizes onlysome of which are coated, plugged or impregnated with selected additivesand as necessary functional, intermediate materials. In some instancesthe plugging additives may comprise a grouping of micro capsules whichmay be of uniform content or mixed content. The micro capsulesinternally contain appropriate beneficial agents which are released upondisintegration of the micro capsule shell wall as a result of contactwith the second component such as an aqueous solvent.

Another slightly more complex additive assembly is identified by thenumeral 182. This assembly is made up of a plurality of spaced apart,porous disc shaped wafers 182a, 182b, 182c and 182d, each wafer being ofthe same or different construction, porosity and interconnecting voidsand each having a multiplicity of reactive sites presenting to theliquid flow specially selected individual species of additives such asbeneficial agents, elements or compounds so that multiple reactivities,and selectivities and sequential separations can be achieved. With thisconstruction, a wide variety of liquid flow rates, and complexsequential separations and priority staged substance introduction intothe system reservoir can be achieved by specially designing each of thewafers having unique affinity attachment and separation characteristicsthat cooperate to make up the functional structural support.

The numeral 184 of FIG. 17 identifies yet another form of the additivemeans of the invention. In this form of the invention, a generallycylindrically shaped functional support means is formed from amultiplicity of reactive sites 184a.

Still another form of the additive assembly is identified in FIG. 17 bythe numeral 186. This micro-particulate assembly comprises acylindrical, porous plug like substrate having a multiplicity ofdeposition sites which are coated with a separation or reactive coatingupon which is deposited an additive such as a biologically activematerial or other beneficial agent.

The base materials for the substrates can include ceramics, carboncomposites, cellulose derivatives, polymers, and a wide variety of othermaterials.

Referring now to FIGS. 26 through 32 and particularly to FIG. 26, yetanother form of the apparatus of the invention for controllablyintermixing the first component and the second liquid component is thereshown. This embodiment is similar to the previously discussed embodimentsave that the container or vial containing the first component isdisposed in the outlet passageway of the container containing the secondcomponent. This embodiment comprises a flexible container 200 having afluid reservoir portion 202 with flexible side walls 202a for containingthe second component. Container 200 is provided with an upper inlet port204 and a lower outlet port assembly 206. In this later form of theinvention, it is to be observed that outlet port assembly 206 ismateable with container assembly 208 which contains the first componentand which extends generally perpendicular to top and bottom edges 200band 200c.

As best seen by also referring to FIG. 30, the container assembly 208 ofthis embodiment of the invention comprises a glass vial 210 whichcarries within its internal chamber 211 a unique additive support 212,or additive presentation means, the details of which will be describedhereinafter. Vial 210 is surrounded by a plastic overcover sheath 214which includes a body portion 214a which encapsulates the non-threadedbody portion 210a of the glass vial. A tear away plastic cap 216sealably encapsulates the threaded, open end 210b of the glass vial(FIG. 26). Circumscribing the upper portion of sheath 214 arecircumferentially spaced locking teeth 217 of the character previouslydescribed and as shown in FIG. 1 for locking the container assembly tothe flexible bag.

Tear-off type cap 216 can be removed from the glass vial assembly bypulling on a tear tab 216a (FIG. 26). Similarly, the lower opening, oroutlet port 206 of the flexible container is initially sealed by asterile tear-off cap 220 of the type illustrated in FIG. 26 and of acharacter well known in the art.

Referring to FIG. 26 it can be seen that after tear-off cover portion216 is removed from the vial assembly, external threads 224 which areprovided on glass vial 210, are exposed. Outlet port assembly 206 ofcontainer 200 is provided with internal threads 226 which cooperate withthreads 224 in the manner shown in FIG. 30.

As best seen in FIG. 27, outlet port assembly 206 of container 200 isprovided with first flow control means for controlling fluid flowoutwardly of the outlet port. The first flow control means is hereprovided as a cap-like closure member 230 having a central downwardlyextending pusher member or pintle 232 which is integrally formed with atop wall 234. Circumscribing top wall 234 is a downwardly dependingskirt 236 which is normally in sealing engagement with an elastomericO-ring 238 provided on a housing assembly 240 which also comprises apart of the first flow control means.

Housing assembly 240 includes a bell-like portion 241 and an integralneck portion 242 which is sealably received within an opening 244provided in bottom wall 200c of the container 200. The previouslymentioned internal threads 226 are provided internally of neck portion242 and are adapted to mateably receive threads 224 on containerassembly 208 when the first and second containers are mated in themanner shown in FIG. 30. Neck portion 242 is also sized totelescopically receive a downwardly depending cylindrical extension 248which is integrally formed with top wall 234 of closure member 230.

Turning to FIG. 28, the open end 210b of vial 210 is normally closed bysecond flow control means which functions to control fluid flow intochamber 211 of the vial which contains support 212. The second flowcontrol means is here provided as an elastomeric closure plug 250,which, in a manner presently to be described, is engageable by pintle232 of closure member 230.

Disposed below plug 250 is a hollow chamber portion 211a within which isprovided circumferentially spaced ribs 252 which function to hold plug250 in position within chamber 211a. Ribs 252 are integrally formed withglass vial 210 (FIG. 29) and function to define fluid flow passageways253 which permit fluid flow around plug 250 when the plug has been movedinto chamber 211a.

Referring to FIGS. 26 and 30, the bottom end of assembly 208 is normallyclosed by tear-away cap 256. A cylindrically shaped rubber filler plug258 is sealably received within opening 210b of glass vial 210. Plug258, as well as a spike port assembly 260 which is receivable withincentral opening 258a of plug 258, form a port of the third flow controlmeans of the invention for controlling fluid flow outwardly of vialassembly 210. As indicated in FIG. 31, spike port assembly 260 includesa hollow body portion 262 and a flange portion 264. Body portion 262 isclosed by a pierceable end wall 262a and a pierceable membrane 265 isbonded to flange 264 to close the central bore 262b of body 262. Body262 and membrane 265 can be constructed from polyvinal chloride or anyother suitable material.

Disposed between the bottom end of additive support 212 and plug 258 isa polymer distribution plug 266 for regulating fluid flow outwardly ofvial 210. Distribution plug 266 has a central bore which is adapted toclosely receive the delivery spike 268 of the delivery means of theinvention which will presently be described. A lower glass frit 267 isprovided between plug 266 and support 212 and an upper glass frit 269 isprovided between the upper end of support 212 and ribs 252. The additiveA which is removably connected to support 212 is, therefore, sandwichedbetween frits 267 and 269 so that liquids flowing through the glass vialwill flow through the glass frits.

In using the apparatus of this latest form of the invention, tear cap216 is first removed from the vial assembly and the flex bag port coveror cap 220 is removed from the outlet port of the flexible bag assembly200 so as to expose the vertically extending mouth of the port in themanner illustrated in FIG. 26. Mating of container assembly 208 with theflex bag assembly 200 is then accomplished by inserting the outboard, orthreaded end of the glass vial 210 into bell shaped portion 241 of theflex bag assembly. Upon insertion of the container assembly into portion241, threads 224 will mate with the internal threads 226 and the openupper end 210a of the vial will move into position to receive the lowerend of pintle 232. Continued rotation of the vial assembly will causethe pintle to push plug 250 downwardly from the first position shown inFIG. 28 into the second position shown in FIG. 30 where the plug hasseated within chamber 211a in the manner shown in FIG. 30. Plug 250 isconstructed so that upon entering chamber 211a, it will expand to adiameter sufficient to prevent it from reseating within opening 210a. Asplug 250 moves downwardly, cap assembly 230 will move upwardly from thefirst position shown in FIG. 27 to the second position shown in FIG. 30.In this second position, skirt 236 will move clear of O-ring 238permitting fluid contained within the flex bag to flow into passageways257 provided in cylindrical portion 248 and then downwardly into vial210 in the manner shown by the arrows in FIG. 30. The fluid will thenflow through glass frit 269, around, about and through the substrate ina manner to remove the additive therefrom by one or more of thepreviously described mechanisms. It should also be noted that as theupper end of the vial moves into threaded engagement with the flex bagoutlet port, the locking teeth 217 provided on plastic cover 214 willlockably engage locking tabs 206a provided on the inner wall of bellshaped portion 241 of the flex bag assembly thereby irreversably lockingthe vial assembly and the flex bag assembly together (FIGS. 29 and 30).

Turning now to FIG. 32, various other forms of adding means of theinvention, in addition to those shown in FIG. 17, are there illustrated.For example, numeral 270 identifies an assembly comprising acylindrically shaped, porous synthetic support with interconnectingvoids, which will permit liquid flow therethrough. Substrate 270 whichcan be constructed from polystyrene, is adapted to removably carry oneor more of the additives previously identified. The selected additivessuch as elements, chemical compounds, drugs and functional intermediatescan be removably attached to the substrate by various techniques wellknown to those skilled in the art. The additives which are removablyaffixed to the substrate are, of course, intermixed with the liquidcomponent, such as a sterile diluent, as the diluent flows from the flexbag interiorly of glass vial 210.

Another form of additive assembly designated in FIG. 32 by the numeral276, comprises an outer tubular porous hydrophylic substrate 277 havingan axially extending bore 279 within which is received a cylindricallyshaped hydrophobic substrate 282. The additives such as chemicalcompounds and beneficial agents, or medicaments are removably affixed tosubstrate 277 in the manner previously described herein. With theconstruction shown, gases can pass through substrate 282 only in thedirection of arrow 273 and liquids can pass through substrate 277 onlyin the direction of arrow 271. In this way, airlock within the flex bagis effectively prevented in a manner which will hereafter be described.

Still another form of additive assembly is identified in FIG. 32 by thenumeral 286. This assembly comprises a tubular, porous hydrophobicmember 287 having a central bore within which is received a cylindrical,porous substrate 289. Substrate 289 provides a scaffold matrix foraffinity attachment of additives of a character presently to bedescribed. Member 287 functions to permit replacement gas flow towardthe liquid reservoir of the flex bag in the direction of arrow 286a ofFIG. 32. Fluid flow of the diluent is permitted in the direction ofarrow 289a.

The numeral 290 of FIG. 32 identifies yet another form of the addingmeans of the invention. In this form of the invention, a generallycylindrically shaped functional support means for affinity attachment,and subsequent release of the additive, is formed from azalactone beadspresenting a multiplicity of reactive sites over a wide area of speciesimmobilization. In this form of the invention, flow rate control meansin the form of a porous media 292 is affixed to one end of thesubstrate. Media 292 functions to control fluid flow toward the outletof the vial assembly and to control residence time of the fluid withinthe substrate 290. A cylindrically shaped member 293, which is disposedwithin bore 290a, functions to permit venting gas to flow toward theflex bag.

Substrate matrices 270, 277, 289, and 290 can be constructed from a widevariety of materials including ceramics, glass, polymers, cellulose,polyacrylamide beads, polyacrylamide gels, dextron based gels, azlactonebeads, and various other materials for synthetic supports of a characterwell known to those skilled in the art including biomosaic polymers.

Turning to FIGS. 26 and 30 the delivery means of the invention fordelivery of the beneficial agent to the patient comprises a deliveryspike assembly 294. This assembly is of a standard construction havingthe previously identified spike 268 over which a protective cover or cap268a can be emplaced (FIG. 26). Spike 268 is connected to a housing 294awhich has a fluid flow outlet 295 in communication with a drip chamber296 which, in turn, is connected to a cannula C. A side arm 297connected to housing 294a functions to provide vent means V forproviding replacement air to the flex bag in a manner well understood bythose skilled in the art.

In use, spike 268 of the spike assembly is inserted into a spike port260 with sufficient force to pierce membrane 265 and end wall 262a inthe manner shown in FIG. 30 so as to open fluid flow betweendistribution plug 266 and the interior fluid flow passageway 268b of thespike. Fluid flowing through the distribution plug enters the flowpassageway of the spike, then flows into drip chamber 296 and then fromthe drip chamber into cannula C.

In this latest form of the invention, the additives which can beremovably affixed to support 212 can take various forms and, aspreviously mentioned, can be removably affixed to the functional supportmeans or support 212 in various ways to enable the use of conventionalseparation techniques as well as the use of separation techniquesbroadly defined by the term chromotography. Chromotography as usedherein refers to a group of separation techniques which arecharacterized by a distribution of the molecules to be separated betweentwo phases, one stationary and other mobile. Affinity chromotographyinvolves the use of biological interactions and contemplates the use ofaffinity chromotography supports through which the eluting fluid flow.In the present embodiment of the invention, the additive presentationmeans assumes the character of an affinity chromotography support towhich various ligands are attached. In the practice of affinitychromotography techniques, one of the members of the pair in theinteraction, the ligand, is immobilized on a solid phase, while theother, the counterligand (most often a protein), is absorbed from theextract that is passing the substrate during the manufacturing process.Importantly, affinity chromotography techniques can include the use of ahighly versatile azlactone functional compounds, such as azlactonefunctional beads, as well as the use of a wide variety of other mediafor activation and coupling chemistry. Examples of ligands that can beattached to the affinity supports include antibodies, enzymes, lectins,nucleic acids hormones and vitamins. Examples of importantcounterligands include antigens, virus, cells, cell surface receptorsand the like. Chromotography and affinity chromotography techniques aredescribed in detail in Protein Purification by Janson and Ryden,Copyright 1989 and reference should be made to his work to provide aworking understanding of the techniques.

Polymeric azlactones are well known in the prior art. Their use in theproduction of homopolymers and copolymers has been described in a numberof patents. See for example, U.S. Pat. No. 3,488,327 (issued Jan. 6,1970 to F. Kollinsky et al.); U.S. Pat. No. 4,304,705 (issued Dec. 8,1981 to S. M. Heilmann et al.); and U.S. Pat. No. 4,737,560 (issued Apr.12, 1988 to S. M. Heilmann et al.); and U.S. Pat. No. 5,013,795 issuedMay 7, 1991 to Coleman, et al.

Azlactones, or oxazolones are cyclic anhydrides of N-acylamino acids andhave been used extensively in organic synthesis. The formation of afive-member azlactone of particularly useful functionality forimmobilization purposes can be accomplished through the reaction of acarboxylate group with a-methyl alanine using a two-step process. (SeeImmobilized Affinity Ligand Techniques-Hermanson, Mallia and Smith,Copyright 1992). One method of forming azlactone beads, the use of whichhas been previously mentioned herein, makes use of this process in thepolymerization of monomers to first yield a carboxyl group on thematrix. In the second step, the azlactone ring is formed in anhydride,alkyl chloroformates, and carbondiimides. The process of forming theseactive groups and of making beaded polymeic supports containing the hasbeen thoroughly described in patents assigned to 3M Corporation (U.S.Pat. Nos. 4,871,824 and 4,737,560). These support materials are notavailable under the tradenames "Emphasis". U.S. Pat. Nos. 5,045,615 and5,013,795 which have been assigned to 3M Corporation also describerecent advances in this technology.

As pointed out in the 3M Corporation U.S. Pat. No. 4,737,560,azlactone-functional polymer beads are useful reactive supports for theattachment of functional materials to provide novel adduct beads. Theadduct beads are useful as complexing agents, catalysts, reagents, andas enzyme or other protein-bearing supports. The term "support" or"affinity support" as used in this sense is usually understood to referto a combination of (1) a ligand (usually of some known molecularconfiguration), that is firmly attached (e.g., immobilized), often bycovalent means, and (2) a matrix (usually a solid insoluble substance).Azlactone support matrix materials and coupling chemistry is also ofspecial interest because of its accessible matrix surface area andeffective ligand diversity that can be attached to that surface.

U.S. Pat. No. 4,072,566 issued to Lynn on Feb. 7, 1978, and entitled"Immobilized Biologically Active Proteins" discloses a method of bondingenzymes or other biologically active proteins to an inorganic supportmaterial using p-phenylenediamine. The support materials disclosed asuseful in the invention include siliceous materials, stannic oxide,titania, manganese dioxide, and zirconia.

The functional support structure 212 of the present embodiment of theinvention can take on the character of an affinity support and as shownin FIGS. 33, 34, 35 and 36 is uniquely constructed to permit enzymes orother biologically active proteins to be bound thereto for laterremoval. This is accomplished by treating functional support 212 in themanner disclosed in the prior art patents identified in the precedingparagraphs with a compound having selective reactive functional groupssuch as azlactone functional compounds. In this way complexing agents,catalysts and biological materials such enzymes, proteins or otheraffinity absorbents, as well as biomacromolecules can be attached to thecarrier for later removal and recovery.

When attaching certain biologically active proteins and other macromolecules, the use of spacer arms or leashes have been found to be verybeneficial (see FIG. 33). Spacer arms or leashes 299 arelow-molecular-weight molecules that are used as intermediary linkersbetween a support material and an affinity ligand L. Usually spacersconsist of linear hydrocarbon chains with functionalities on both endsof each coupling to the support and ligand. First, one end of the spaceris attached chemically to the matrix using traditional immobilizationchemistries and the other end is connected subsequently to the ligandusing a secondary coupling procedure. The result is an immobilizedligand that sticks out from the matrix backbone by a distance equal tothe length of the spacer arm chosen.

The principal advantage of using a spacer arm is that it provides ligandaccessibility to the binding site S of a target molecule. When thetarget molecule is a protein with a binding site somewhat beneath itsouter surface (upper portion of FIG. 33), a spacer is essential toextend the ligand out far enough from the matrix to allow interaction.When the ligand binding site is buried or is disposed in a pocketlocated just below the surface of the protein, a ligand that is eitherbelow the surface of the support material or a ligand that is attacheddirectly to the surface cannot reach the level of the binding site on anapproaching protein molecule. The result may be weakened interaction orno binding at all. Accordingly, in these instances, a spacer arm isrequired to provide the ligand accessibility to the binding site of theprotein molecule. The details covering the use of spacer arms are fullyset forth in Section 3.1.1 of the work entitled Immobilized AffinityLigand Techniques. This Section 3.1.1 is incorporated herein byreference.

It is to be noted that an immobilized protein P can also be used toimmobilize an antibody molecule (FIG. 35) by taking advantage of thenatural affinity of the protein for immunoglobulins. Incubation of aspecific antibody with the protein matrix will bind the antibody in theFe region, away from the antigen binding sites (FIG. 36). Subsequentcross-linking of this complex with DMP (dimethyl pimelimidate) yields acovalently attached antibody with the antigen binding sites facingoutward and free to interact with antigen.

With rigid support matrix materials, a spacer molecule may also providegreater flexibility, allowing the immobilized ligand to move intoposition to establish the correct binding orientation with a protein.The degrees of freedom that a hydrocarbon extender can provide are muchgreater than the movement possible within the polymeric backbone of amatrix.

The choice of spacer molecule can affect the relative hydrophilicity ofthe immediate environment of an immobilized ligand. Molecules containinglong hydrocarbon chains may increase the potential for nonspecifichydrophobic interactions, especially when the affinity ligand is smalland of low molecular weight. Selecting spacers that have more polarconstituents, such as secondary amines, amide linkages, ether groups orhydroxyls will help keep hydrophobic effects at a minimum.

It is important to recognize that, as used in the present form of theinvention, affinity supports are now capable of total binding capacityat a level that enables attachment to the support of additives insubstantial amounts for subsequent release recovery and infusion ofbeneficial agents in a manner which can be therapeutically efficaciousto a patient. Alternate disassociation constants for desorption of theabsorbed component from the affinity matrix can be established so as tocritically determine the optimal conditions for elution of the boundadditives over time. The elution diluent acts as the desorption agentwhen exposure of the elution agent to the substrate breaks the affinityattachment bond as a function of time.

Having now described the invention in detail in accordance with therequirements of the patent statutes, those skilled in this art will haveno difficulty in making changes and modifications in the individualparts or their relative assembly in order to meet specific requirementsor conditions. Such changes and modifications may be made withoutdeparting from the scope and spirit of the invention, as set forth inthe following claims.

I claim:
 1. An apparatus for controllably intermixing a first componentand a second liquid component comprising:(a) a first container having afluid reservoir for containing the second component and an outletassembly having a fluid outlet in fluid communication with said fluidreservoir and first flow control means for normally closing said fluidoutlet, said first flow control means being movable into a fluid outletopening position; (b) adding means for presenting the first component tothe second component for intermixing therewith, comprising:(i) a supportupon which the first component is removably affixed; (ii) a secondcontainer for containing said support, said second container having aplug receiving chamber; and (iii) connector means for directlyconnecting said second container to said outlet assembly of said firstcontainer so that said support can be exposed to fluid flowing out ofsaid fluid outlet of said container; and (c) second flow control meansfor controlling the flow of fluid into said second container, saidsecond flow control means comprising a closure plug engageable by saidfirst flow control means as said second container is connected to saidoutlet assembly, to move said closure plug into said plug receivingchamber and simultaneously to move said first flow control means intosaid fluid outlet opening position whereby fluid can flow toward saidadding means.
 2. An apparatus as defined in claim 1 in which said firstcomponent comprises a beneficial agent and in which said secondcomponent comprises a parenteral fluid.
 3. An apparatus as defined inclaim 1 in which said first component comprises a drug and in which saidsecond component comprises a diluent.
 4. An apparatus as defined inclaim 1 in which said first component comprises a biologically activematerial.
 5. An apparatus as defined in claim 1 in which said firstcomponent is removable from said support using affinity chromotographytechniques.
 6. An apparatus as defined in claim 5 in which said firstcomponent is connected to said support using azlactone functionalcompounds.
 7. An apparatus as defined in claim 6 in which said firstcomponent comprises a protein.
 8. An apparatus for controllablyintermixing a first component and a second liquid componentcomprising:(a) a flexible container having a fluid reservoir forcontaining the second liquid component and a fluid outlet assemblyhaving a fluid outlet having first threads said fluid outlet being influid communication with said fluid reservoir and first flow controlmeans for controlling fluid flow through said fluid outlet, said firstflow control means comprising a closure assembly having a closure capfor closing said fluid outlet and a pintle connected to said closurecap, said closure cap being movable from a first fluid outlet closingposition to a second fluid outlet opening position; (b) adding means forpresenting the first component to the second component for intermixingtherewith, comprising:(i) a support upon which the first component isremovably affixed; (ii) a vial for containing said support said vialhaving second threads mateable with said first threads and a plugreceiving chamber; and (iii) connector means for directly connectingsaid vial to said fluid outlet assembly of said flexible container sothat said support is exposed to fluid flowing through said fluid outlet,said connector means comprising threads provided on said vial forthreadable interconnection with threads provided proximate said fluidoutlet of said flexible container; (c) second flow control means forcontrolling the flow of fluid into said vial, said second flow controlmeans comprising a closure plug engageable by said pintle as said vialis connected to said fluid outlet assembly to move said closure plugfrom a first inlet closing position into an inlet opening positionwherein said plug is moved into said plug receiving chamber andsimultaneously to move said closure cap toward said second open positionwhereby the liquid contained within said flexible container can flowfrom said fluid reservoir into said vial containing said support.
 9. Anapparatus as defined in claim 8 in which said first component comprisesa biologically active material.
 10. An apparatus as defined in claim 8in which said first component comprises a drug.
 11. An apparatus asdefined in claim 8 in which said second component comprises a diluent.12. An apparatus for controllably intermixing a first component and asecond liquid component comprising:(a) a flexible container having top,bottom and side portions and including a fluid reservoir for containingthe second component and a fluid outlet assembly connected to saidbottom portion having a fluid outlet in fluid communication with saidfluid reservoir, said fluid outlet assembly having internal threads andfirst flow control means for controlling fluid flow through said fluidoutlet; (b) adding means for presenting the first component to thesecond liquid component for intermixing therewith, comprising:(i) a vialincluding an internal chamber having a fluid inlet and being providedwith external threads mateable with said internal threads of said fluidoutlet assembly, said vial having second flow control means forcontrolling the flow of liquid into said internal chamber, said secondflow control means being operable by said first flow control means ofsaid fluid outlet assembly; and (ii) adding means contained within saidinternal chamber said adding means comprising said first component and apresentation means for presenting said first component to said secondcomponent as said second component flows through said internal chamber,said presentation means comprising a porous support said first componentbeing immobilized on said porous support and is removable therefromusing affinity chromotography techniques.
 13. A device as defined inclaim 12 in which a ligand is connected to said support and a targetmolecule is connected to said ligand.
 14. A device as defined in claim13 in which a spacer arm is connected to said support and in which aligand is connected to said spacer arm.
 15. A device as defined in claim14 in which an enzyme is connected to said target molecule.
 16. A deviceas defined in claim 15 in which said target molecule is a protein. 17.An apparatus as defined in claim 16 in which said first flow controlmeans comprises a closure cap for closing said fluid outlet and a pintleconnected to said closure cap.
 18. An apparatus as defined in claim 17in which said second flow control means comprises a closure plug forclosing said fluid inlet of said internal chamber, said closure plugbeing engagable by said pintle to move said closure plug from a firstinlet closing position to a second inlet opening position wherein saidclosure plug is disposed within said internal chamber of said vial. 19.An apparatus as defined in claim 18 in which said vial is provided witha fluid outlet having third closure means for closing said fluid outlet.20. An apparatus as defined in claim 19 in which said third closuremeans comprises a pierceable membrane closing said fluid outlet.
 21. Anapparatus as defined in claim 20 further including delivery means fordelivering the intermixed first and second components to a patient, saiddelivery means comprising delivery spike assembly having a spikeprovided with a fluid passageway and a cannula connected to said spike,said spike being adapted to penetrate said pierceable membrane wherebythe intermixed first and second components can flow from said internalchamber of said vial into said fluid passageway of said spike.
 22. Anapparatus for controllably intermixing a first component and a secondliquid component comprising:(a) a container having a fluid reservoir forcontaining the second liquid component and a fluid outlet assemblyhaving a fluid outlet in fluid communication with said fluid reservoirand first flow control means for controlling fluid flow through saidfluid outlet, said first flow control means comprising closure means fornormally closing said fluid outlet, said closure means being movablefrom a first fluid outlet closing position to a second fluid outletopening position; (b) adding means for presenting the first component tothe second component for intermixing therewith, comprising:(i) a supportupon which the first component is removably affixed; (ii) a vial forcontaining said support, said vial having a plug receiving chamber andbeing mateable with said fluid outlet assembly for moving said firstflow control means toward said second fluid outlet opening position; and(iii) connector means for directly connecting said vial to said fluidoutlet assembly of said flexible container so that said support can beexposed to fluid flowing through said fluid outlet; and (c) second flowcontrol means for controlling the flow of fluid into said vial, saidsecond flow control means comprising a closure plug and cooperating withsaid first flow control means to move said closure plug from a firstinlet closing position into an inlet opening position wherein said plugis moved into said plug receiving chamber of said vial as said firstflow control means is moved toward said second fluid outlet openingposition, whereby the liquid contained within said container can flowfrom said fluid reservoir into said vial container said support.
 23. Anapparatus as defined in claim 22 in which said first flow control meanscomprises a closure cap for closing said fluid outlet and a pintleconnected to said closure cap, said closure plug being engageable bysaid pintle to move said closure plug from a first inlet closingposition and into said plug receiving chamber of said vial.
 24. Anapparatus as defined in claim 22 in which said first component comprisesa biologically active material.
 25. An apparatus as defined in claim 22in which said first component is removable from said support usingaffinity chromotography techniques.
 26. An apparatus as defined in claim25 in which said first component is connected to said support usingazlactone functional compounds.
 27. A device as defined in claim 26 inwhich a ligand is connected to said support and a target molecule isconnected to said ligand.
 28. A device as defined in claim 27 in which aspacer arm is connected to said support and in which a ligand isconnected to said spacer arm.
 29. A device as defined in claim 28 inwhich an enzyme is connected to said target molecule.
 30. A device asdefined in claim 29 in which said target molecule is a protein.